Decalcifying heart valve

ABSTRACT

Vascular valve systems for treating calcified vascular vessel valves by delivery of one or more calcium chelating agents are described. Methods of making the vascular valve systems are also described.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority under 35 USC §119(e) to U.S.Provisional Patent Application Ser. No. 61/569,961, filed on Dec. 13,2011, the entire contents of which are hereby incorporated by reference.

TECHNICAL FIELD

This invention relates to vascular valve systems, more particular tovascular valve systems that can remove calcification.

BACKGROUND

Without wishing to be bound by theory, it is believed that placing anartificial heart valve by a transcatheter aortic-valve implantation(“TAVI”) procedure can lead to a higher risk for stroke, resulting frompieces of calcification being released from the original heart valve.However, release of calcium deposits often may not occur during theprocedure, but during the days following the procedure. This can occurwhen calcium deposits are broken into many pieces during the procedure,but are not immediately released from the initial valve surfaces.Instead, small pieces of calcium deposits can hang loose and be releasedat a later time due to continuous movement of the valve. For thisreason, treating the calcium deposits before they are released into theblood stream can be important to the long term success of atranscatheter aortic-valve implantation procedure.

SUMMARY

In one aspect, the disclosure features a vascular valve system includingan expandable stent that includes an outer surface and a lumen; a valvethat includes a plurality of leaflets; and a layer disposed on at leasta portion of the outer surface of the stent. The valve is disposedwithin the lumen and coupled to the expandable stent. The layer includesa hydrogel, a calcium-chelating agent, and an acidifying agent.

In another aspect, the disclosure features a vascular valve systemincluding an expandable stent that includes an outer surface and alumen; a valve comprising a plurality of leaflets; and a permeablehousing disposed on one or more leaflets, or around a portion of theouter surface of the stent, or both. The valve is disposed within thelumen and coupled to the expandable stent. The disclosure furtherfeatures a method of replacing a heart valve, including implanting thevascular valve system, and injecting a solution comprising a hydrogel, acalcium-chelating agent, and an acidifying agent into the permeablehousing.

Embodiments of the above-mentioned aspects can have one or more of thefollowing features.

In some embodiments, the valve includes at least two leaflets (e.g.,three leaflets). The valve can include porcine pericardium or apolymeric material. The valve can be attached to the stent with aplurality of sutures. The layer can be disposed around a circumferenceof the valve. The hydrogel can be in the form of a plurality of fibers,a coating, a sheet, a film, or a viscous liquid. In some embodiments,the hydrogel is selected from the group consisting ofoligo(amidoamine/β-amino ester), methyl cellulose, collagen, gelatin,chitosan, hyaluronic acid, chondroitin sulfate, alginate, agar, agarose,fibrin, albumin, polyethylene glycol, polyethylene oxide, polyvinylalcohol, polypropylene fumarate), oligo(polyethylene glycol) fumarate,poly(N-isopropylacrylamide), polypropylene oxide, poly(aldehydeguluronate), polylactic acid, polyglycolic acid,poly(lactic-co-glycolic) acid, polyanhydride, combinations thereof, andcopolymers thereof.

In some embodiments, the calcium-chelating agent is selected from thegroup consisting of ethylene diamine tetraacetic acid, phosphonates,1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, ethyleneglycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid,trans-1,2-cyclohexanediaminetetraacetic acid,N-hydroxyethylenediaminetriacetic acid, diethylenetriaminepentaaceticacid, and glycine. The calcium-chelating agent can be covalently boundto the hydrogel. The hydrogel can include from one percent to tenpercent by weight of the calcium-chelating agent.

In some embodiments, the acidifying agent is selected from the groupconsisting of citric acid, ascorbic acid, acetic acid, lactic acid, andany combination thereof. The acidifying agent can be covalently bound tothe hydrogel. The hydrogel can include from 0.5 percent to 20 percent byweight of the acidifying agent.

In some embodiments, the hydrogel is crosslinkable. The hydrogel caninclude polyethylene glycol diacrylate and poly(ethyleneglycol)dimethacrylate.

In some embodiments, the permeable housing is disposed around acircumference of the valve. A hydrogel, a calcium-chelating agent, andan acidifying agent can be disposed within the housing. The vascularvalve system can further include a layer disposed on at least a portionof the outer surface of the stent, the layer including a hydrogel, acalcium-chelating agent, and an acidifying agent.

Embodiments and/or aspects can provide one or more of the followingadvantages.

In some embodiments, the hydrogel can immobilize loose calciumfragments, while the calcium chelators can subsequently chelate (e.g.,bind to) and solubilize the fragments, such that the chelated calciumcan be removed in a body fluid. In some embodiments, when the valvesystem includes hydrogel fibers, the fibers can provide a deformableopen structure that can conform to a space around the valve, whileacting at the same time as a network in which large debris can becaptured. The open structure can allow access to plasma and endothelialprogenitor cells, which can assist in covering the replaced nativevalve.

In some embodiments, when the hydrogel is in the form of a coating,sheet, or film, the coating, sheet, or film can be continuous ordiscontinuous, have perforations at regular or irregular intervals andof any size and/or shape, and/or can have variable thickness from oneregion to another.

In some embodiments, the film, coating, or sheet can provide increasedstorage volume for chelators, compared to a fiber network. In someembodiments, a film can allow for dissolution and removal of calciumdeposits by, for example, chelation of the calcium deposits.

In some embodiments, when the hydrogel is in the form of a liquid, alarger volume of a liquid can be delivered compared to a hydrogel film,coating, or sheet, or a fiber system. A liquid can provide greateradaptability (e.g., can conform to) to open volumes around the implantedvalve.

In some embodiments, the housing or the hydrogel layer can span thethickness of the valve, and when implanted, can fully cover a nativevalve that is now positioned between a body vessel and the heart valvesystem.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 shows an embodiment of a vascular valve system.

FIG. 2 shows an embodiment of a vascular valve system.

FIG. 3 shows an embodiment of a vascular valve system.

FIG. 4 shows an embodiment of a vascular valve system.

FIGS. 5A-5B shows an embodiment of a vascular valve system. FIG. 5A is amagnified view of a stent strut. FIG. 5B is a magnified cross-sectionalview of a stent strut.

FIGS. 6A-6B shows an embodiment of a vascular valve system.

FIG. 7 shows an embodiment of a vascular valve system.

FIG. 8 shows an embodiment of a vascular valve system.

Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION

Referring to FIG. 1, in some embodiments, implantable heart valvesystems 10 include a tubular expandable stent, which includes an outersurface 12 and a lumen 14. The lumen can include a valve 16 that has aplurality of leaflets (e.g., 18, 18′, 18″) attached to the expandablestent via, for example, a plurality of sutures, a glue, or by heatbonding (e.g., laser welding). Valve 16 can be formed of, for example,porcine pericardium or a polymeric material. A soft hydrogel 20 loadedwith calcium chelators (e.g., calcium chelating agent) 22 can bedisposed on the outside of implantable heart valve systems. The hydrogelcan immobilize loose calcium fragments, while the calcium chelators cansubsequently chelate (e.g., bind to) and solubilize the fragments, suchthat the chelated calcium can be removed in a body fluid.

In some embodiments, referring to FIG. 2, the hydrogel coating caninclude a network of fibers 24 (e.g., electrospun fibers) positioned onthe outside of the valve housing. Chelators 22 (not shown) can form partof the fibers, and/or the space between the fibers can be filled withchelators. For example, ion-exchange/chelating functionalities can beincorporated into a polymer matrix of the hydrogel or hydrogel fibers bypolymerization, co-polymerization, and/or grafting. As another example,chelating agents such as ethylenediamine tetraacetic acid (EDTA) andamino acids (e.g., aspartic acid, glutamic acid, molecules containingaspartic and/or glutamic acid such as poly(asparticacid-co-aminocarboxylic acid), alkylamine-modified polyaspartic acid)can be encapsulated and uniformly dispersed within the outer hydrogelcoating.

The hydrogel coating can include acidic functionalities, such that at anion-exchange (chelating) polymer/calcified plaque interface there can bea local change in pH. The acidic functionalities can be the same ordifferent from the calcium chelators. Chelators that can also provide anacidic environment can include, for example, ethylenediamine tetraaceticacid (EDTA) and molecules including other amino (imino) acid functionalgroups such as N-hydroxyethylenediaminetriacetic acid (HEDTA),diethylenetriaminepentaacetic acid (DTPA), and glycine. In someembodiments, a change in local pH (e.g., a decrease in local pH) caninitiate a conversion of insoluble CaCO₃ into soluble calciumbicarbonate. Thus, a Ca²⁺ cation can be easily captured byion-exchange/chelating groups incorporated within the polymeric stentcoating layer. In some embodiments, to enhance an acidic environment,acidic molecules such as ascorbic acid (vitamin C) can be incorporatedinto the hydrogel coating.

In some embodiments, the hydrogel layer can be positioned on the outsidesurface of the tubular expandable stent, around a circumference of thevalve. The hydrogel layer can span the entire length of the tubularexpandable stent, or span less than the entire length (e.g., up to about90%, up to about 80%, up to about 70%, up to about 60%, up to about 50%,up to about 40%, up to about 30%, up to about 20%, or up to about 10% ofthe full length) of the tubular expandable stent, so long as thehydrogel layer covers a length around the circumference of the valve.The hydrogel layer can span the thickness of the valve, and whenimplanted, can fully cover a native valve that is now positioned betweena body vessel and the heart valve system. In some embodiments, thehydrogel layer spans less than the full circumference of the tubularexpandable stent, and gaps can exist between regions of the hydrogellayer. For example, the hydrogel layer can span up to about 80% (up toabout 85%, up to about 90%, up to about 95%, up to about 99%) of thefull circumference of the tubular expandable stent.

In some embodiments, the hydrogel is in the form of fibers, coatings,sheets, films, or viscous liquids, or a combination thereof. The fiberscan have a sub-micron (e.g., less than one micron) width or diameter. Insome embodiments, the fibers can have an average width or diameter fromabout five nm to about 500 nm. For example, the average width ordiameter of the fibers can be greater than or equal to about five nm(e.g., greater than or equal to about 10 nm, greater than or equal toabout 25 nm, greater than or equal to about 50 nm, greater than or equalto about 75 nm, greater than or equal to about 100 nm, greater than orequal to about 125 nm, greater than or equal to about 150 nm, greaterthan or equal to about 175 nm, greater than or equal to about 200 nm,greater than or equal to about 225 nm, greater than or equal to about250 nm, greater than or equal to about 300 nm, greater than or equal toabout 350 nm, greater than or equal to about 400 nm, or greater than orequal to about 450 nm); and/or less than or equal to about 500 nm (e.g.,less than or equal to about 450 nm, less than or equal to about 400 nm,less than or equal to about 350 nm, less than or equal to about 300 nm,less than or equal to about 250 nm, less than or equal to about 225 nm,less than or equal to about 200 nm, less than or equal to about 175 nm,less than or equal to about 150 nm, less than or equal to about 125 nm,less than or equal to about 100 nm, less than or equal to about 75 nm,less than or equal to about 50 nm, less than or equal to about 25 nm, orless than or equal to about 10 nm). Fibers can provide a deformable openstructure that can conform to a space around the valve, while acting atthe same time as a network in which large debris can be captured. Theopen structure can allow access to plasma and endothelial progenitorcells, which can assist in covering the replaced native valve. In someembodiments, a fiber-network can form a barrier that captureslarge-particles and allows small particles (e.g., particles having anaverage maximum dimension of less than or equal to about 50 micrometers)to be removed by the bloodstream, where the open structure can allow thecaptured particles to be overgrown, encapsulated, and/or fixed by acells.

The width or diameter of the hydrogel fibers can be substantiallyuniform along a length of a fiber, e.g., varying from about ±1 percentto about ±25 percent of the average width or diameter value over a fiberlength. In some embodiments, a fiber is not perfectly circular incross-section (e.g., oval, elliptical, regularly polygonal, orirregularly polygonal in cross section). The average width or diameterof the fiber having an irregular cross-section along a given length canrefer to an average distance of any two orthogonal lines that both passthrough the geometric center of the fiber cross-section and have endpoints on the perimeter of the fiber, or to the distance of any one suchline.

In some embodiments, the fibers can have a length from about 10 μm toabout 10 cm. For example, the fiber length can be greater than or equalto about 10 μm (e.g., greater than or equal to about 50 μm, greater thanor equal to about 100 μm, greater than or equal to about 150 μm, greaterthan or equal to about 500 μm, greater than or equal to about 1 mm,greater than or equal to about 5 mm, greater than or equal to about 1cm, greater than or equal to about 2 cm, greater than or equal to about3 cm, greater than or equal to about 4 cm, greater than or equal toabout 5 cm, greater than or equal to about 7 cm, greater than or equalto about 8 cm, or greater than or equal to about 9 cm); and/or less thanor equal to about 10 cm (e.g., less than or equal to about 9 cm, lessthan or equal to about 8 cm, less than or equal to about 7 cm, less thanor equal to about 5 cm, less than or equal to about 4 cm, less than orequal to about 3 cm, less than or equal to about 2 cm, less than orequal to about 1 cm, less than or equal to about 5 mm, less than orequal to about 1 mm, less than or equal to about 500 μm, less than orequal to about 150 μm, less than or equal to about 100 μm, or less thanor equal to about 50 μm).

In some embodiments, when the hydrogel is in the form of a coating, asheet, or a film, the hydrogel can have a thickness of from about 10micrometers (e.g., from about 25 micrometers, from about 50 micrometers,from about 100 micrometers, from about 150 micrometers, from about 200micrometers, from about 250 micrometers, from about 300 micrometers,from about 350 micrometers, from about 400 micrometers, or from about450 micrometers) to about 500 micrometers (e.g., to about 450micrometers, to about 400 micrometers, to about 350 micrometers, toabout 300 micrometers, to about 250 micrometers, to about 200micrometers, to about 150 micrometers, to about 100 micrometers, toabout 50 micrometers, or to about 25 micrometers). For example, thehydrogel coating, sheet, or film can have a thickness greater than orequal to about 100 micrometers (e.g., greater than about 125micrometers, greater than about 150 micrometers, greater than about 175micrometers, greater than about 200 micrometers, or greater than orequal to about 225 micrometers) and/or less than or equal to about 250micrometer (e.g., less than or equal to about 225 micrometers, less thanor equal to about 200 micrometers, less than or equal to about 175micrometers, less than or equal to about 150 micrometers, or less thanor equal to about 125 micrometers). The coating, sheet, or film can becontinuous or discontinuous, have perforations at regular or irregularintervals and of any size and/or shape, and/or can have variablethickness from one region to another. In some embodiments, the film,coating, or sheet can provide increased storage volume for chelators,compared to a fiber network. In some embodiments, a film can allow fordissolution and removal of calcium deposits by, for example, chelationof the calcium deposits.

In some embodiments, the hydrogel is in the form of a viscous liquid.The liquid can have a viscosity of from about 100 centipoise (e.g., fromabout 250 centipoise, from about 500 centipoise, from about 750centipoise, from about 1000 centipoise, from about 1250 centipoise, fromabout 1500 centipoise, or from about 1750 centipoise) to about 2000centipoise (e.g., to about 1750 centipoise, to about 1500 centipoise, toabout 1250 centipoise, to about 1000 centipoise, to about 750centipoise, to about 500 centipoise, or to about 250 centipoise). Forexample, the hydrogel viscous liquid can have a viscosity greater thanor equal to about 500 centipoise (e.g., greater than or equal to about600 centipoise, greater than or equal to about 700 centipoise, greaterthan or equal to about 800 centipoise, or greater than or equal to about900 centipoise) and/or less than or equal to about 1000 centipoise(e.g., less than or equal to 900 centipoise, less than or equal to about800 centipoise, less than or equal to about 700 centipoise, or less thanor equal to about 600 centipoise). In some embodiments, a larger volumeof a liquid can be delivered compared to a hydrogel film, coating, orsheet, or a fiber system. A liquid can provide greater adaptability(e.g., can conform to) to open volumes around the implanted valve.

In some embodiments, when a liquid contains monomers or oligomers, themonomers or oligomers can have reactive end groups that can be furtherpolymerized (e.g., crosslinked) by physical or chemical crosslinkingExamples of reactive end groups can include, for example, hydroxyl,allyl, amine, isocyanate, cyano, carboxylate, anhydride, halide, silane,thiol, azide, activated ester, acrylate, and/or aldehyde. For example,chemical crosslinking can occur by photopolymerization. In someembodiments, physical crosslinking can occur by stereocomplexation oftwo or more types of molecules. For example, stereocomplexed hydrogelscan be obtained by mixing aqueous solutions of molecules grafted withL-lactic acid oligomers and D-lactic acid oligomers. In someembodiments, without wishing to be bound by theory, it is believed thatgelation can occur due to stereocomplex formation of oligomers ofopposite chirality (e.g., D- and L-lactic acids). In some embodiments,stereocomplexation hydrogels can occur with water-solublepoly(L-lactide) and poly(D-lactide) copolymers or dextran-lactidehydrogels. Examples of stereocomplexation is described, for example, inJun et al., Macromolecular Research, 16 (8), 704-710 (2008), hereinincorporated by reference. In some embodiments, a liquid can contain agel that is fluid at lower temperatures (e.g., below 30° C.) and thatgelates at higher temperatures (e.g., from 30 to 37° C.). The liquidcan, for example, contain a temperature-responsive polymer such aspolyacrylamide, polymethacrylamide and/or poly(N-isopropylacrylamide).

The hydrogel can include natural and/or synthetic polymers, such asoligo(amidoamine/β-amino ester), methyl cellulose, collagen, gelatin,chitosan, hyaluronic acid, chondroitin sulfate, alginate, agar, agarose,fibrin, polyethylene glycol, polyethylene oxide, polyvinyl alcohol,polypropylene fumarate), oligo(polyethylene glycol) fumarate,poly(N-isopropylacrylamide), polypropylene oxide, poly(aldehydeguluronate), polylactic acid, polyglycolic acid,poly(lactic-co-glycolic) acid, polyanhydride (e.g., poly(sebacicacid-co-1,3-bis(p-carboxyphenoxy) propane) (P(CPP-SA)), combinationsthereof, and/or copolymers thereof. Examples of polyanhydrides aredescribed, for example, in Kumar et al., Advanced Drug Delivery Reviews54, 889-910 (2002).

In some embodiments, the hydrogel can include frangible capsules (e.g.,microcapsules) that can rupture upon application of a critical pressure.The microcapsules can enclose one or more therapeutic agents, one ormore acidifying agents, and/or one or more calcium-chelating agents. Insome embodiments, the capsules can rupture upon delivery and expansionof a vascular valve system to deliver encapsulated agents. Themicrocapsules can have a multilayer polyelectrolyte shell. In someembodiments, the capsules are ceramic capsules. Frangible capsules,critical pressures, and methods of making and delivering frangiblecapsules are described, for example, in U.S. Pat. No. 7,364,585 and U.S.Application Ser. No. 61/421,054, filed Dec. 8, 2010, each hereinincorporated by reference in its entirety.

Without wishing to be bound by theory, it is believed that ion exchangeprocesses using acidic or Na⁺ cation exchangers can remove calcium froma variety of media. For example, a number of ion-exchange or chelatingfunctional groups can selectively bind calcium and be used for calciumremoval. Functional groups such as amino diacetic acid and—CH₂—NH—CH₂—PO₃Na are used in commercially microporous resin products(e.g., Ionac SR-5 and Amberlite IRC 747) for calcium extraction/removal,respectively. In some embodiments, ethylenediamine tetraacetic acid(EDTA) and other amino acid derivatives (e.g.,N-hydroxyethylenediaminetriacetic acid (HEDTA),diethylenetriaminepentaacetic acid (DTPA) and glycine) can be efficientchelating agents for calcium. Other chemical compounds that can act ascalcium binders include, for example, citric acids and phosphonates(e.g., HPDP (1-hydroxo-3-aminopropane-1,1-diphosphonate), or HEDP(hydroxyethyl-1,1-diphosphonate)).

In some embodiments, the calcium-chelating agent includesethylenediamine tetraacetic acid, phosphonates,1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, ethyleneglycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid,trans-1,2-cyclohexanediaminetetraacetic acid,N-hydroxyethylenediaminetriacetic acid (HEDTA),diethylenetriaminepentaacetic acid (DTPA), glycine, 2,2′-bipyridyl,dimercaptopropanol, ionophores, nitrilotriacetic acid, NTAortho-phenanthroline, gramicidin, monensin, valinomycin, salicylic acid,triethanolamine (TEA), polysaccharides, organic acids with at least twocoordination groups (e.g., citric acid, or citric acid together withacetic acid), lipids, steroids, amino acids, peptides, phosphates,nucleotides, tetrapyrrole, ferrioxamines, and/or phenolics. Thecalcium-chelating agent can be used singly or in combination, and/or canbe delivered to the area surrounding and including a calcified valve.The calcium-chelating agent can be in the form of microparticles,nanoparticles, or nanocrystals; or microspheres or nanospherescontaining or bound to one or more chelating agents. The microspheres ornanospheres can include one or more biocompatible materials such aspolylactic acid, polyamide esters, polyvinyl esters, polyvinyl alcohol,polyanhydrides, natural biodegradable polymers, polysaccharides, andderivatives thereof. The calcium-chelating agent can be covalentlybound, ionically bound, and/or physically adsorbed to the hydrogel.Examples of covalent bonds include, for example, enzyme andhydrolytically cleavable bonds such as ester, amide, anhydride, andcarbamide linkages, and/or acid-cleavable groups such as —OC(O)—,—C(O)O—, or —C═NN—. In some embodiments, a calcium-chelating agent isdissolved in a hydrogel.

In some embodiments, the hydrogel includes from about one percent (e.g.,from about two percent, from about three percent, from about fourpercent, from about five percent, from about six percent, from aboutseven percent, from about eight percent, or from about nine percent) toabout 10 percent (e.g., to about nine percent, to about eight percent,to about seven percent, to about six percent, to about five percent, toabout four percent, to about three percent, or to about two percent) byweight of the calcium-chelating agent.

In some embodiments, the acidifying agent includes citric acid, ascorbicacid, acetic acid, and/or lactic acid. The acidifying agent can becovalently bound, ionically bound, and/or physically adsorbed to thehydrogel. The acidifying agent can be in the form of microparticles,nanoparticles, or nanocrystals; or microspheres or nanospherescontaining or bound to one or more acidifying agents. In someembodiments, the hydrogel includes from about 0.5% percent (e.g., fromabout one percent, from about two percent, from about five percent, fromabout seven percent, from about 10 percent, from about 15 percent, orfrom about 17 percent) to about 20% (e.g., to about 17 percent, to about15 percent, to about 10 percent, to about seven percent, to about fivepercent, to about two percent, or to about one percent) of theacidifying agent.

Referring to FIG. 3, in some embodiments, instead of coating a heartvalve system 200 with a hydrogel including calcium chelators and/oracidifying agents, a hydrogel composition 222 can be injected into ahousing 220, between the heart valve system and vessel wall 230. Theheart valve system 200 can include a prosthetic valve having a pluralityof leaflets 218, 218′, and 218″, within a lumen 214 of an expandablestent 212. The hydrogel composition can be biodegradable. In someembodiments, the hydrogel composition includes, for example,oligo(amidoamine/β-amino ester), gelatins, collagen, chitosan,hyaluronic acid, chondroitin sulfate, alginate, agar, agarose, fibrin,polyethylene glycol, polyethylene oxide, polyvinyl alcohol,polypropylene fumarate), oligo(polyethylene glycol) fumarate,poly(N-isopropylacrylamide), polypropylene oxide, poly(aldehydeguluronate), polylactic acid, polyglycolic acid,poly(lactic-co-glycolic) acid, and/or polyanhydride. Examples ofinjectable hydrogels are described, for example, in Tan et al.,Materials 2010, 3, 1746-1767, herein incorporated by reference. Thehousing can be permeable, such that hydrogel compositions, calciumparticles, and bodily fluids can flow into and chelated molecules canflow out of the housing. In some embodiments, the housing is dissolvableor absorbable.

In some embodiments, the housing is porous. The pores can allow areasonable quick flow or interaction with the environment. In someembodiments, a high density of pores can allow for quick flow orinteraction with the environment. For example, the housing can includepores (e.g., laser ablated pores) having an average diameter of fromabout 10 micrometers (e.g., from about 25 micrometers, from about 50micrometers, or from about 75 micrometers) to about 100 micrometers(e.g., to about 75 micrometers, to about 50 micrometers, or to about 25micrometers). As used herein, a density of pores on a housing is an areaof porous area over a total surface area of a housing. In someembodiments, the pore density can be from about five percent (e.g., fromabout 10 percent, from about 15 percent, from about 20 percent, fromabout 25 percent, from about 30 percent, from about 35 percent, fromabout 40 percent, or from about 45 percent) to about 50 percent (e.g.,to about 45 percent, to about 40 percent, to about 35 percent, to about30 percent, to about 25 percent, to about 20 percent, to about 15percent, or to about 10 percent).

The housing can be disposed within or on the outside of a heart valvesystem. For example, in some embodiments, a housing can be disposed onan inside wall of a heart valve system, and a fiber spun network can bedisposed on an outside surface of the heart valve system. Referring toFIG. 4, a heart valve system 300 can have housing 310 in the form ofpockets including chelators and/or therapeutic agent on replacementheart valves 320. The valves can function while minimally mechanicallyaffected by the pockets. As shown in FIG. 4, the heart valve system canhave a fiber network 330 on the exterior surface of the system, whichcan, for example, capture larger calcified deposits or plaques. Housings310 can be filled after the heart valve system has been implanted. Thehousings on the inner side of the valve can minimize interference with ablood stream going to the aortic arteries. In some embodiments, thehousing can include a double layer of polymer, for example, a polymericfirst layer (e.g., polyurethane, PLGA) covering on a valve housingsecond layer. In some embodiments, the housing can include thinguidewires that are inserted into the housing (pockets) and through thedelivery catheter, such that an injection catheter can be guided overthese wires into the empty pockets and inject a hydrogel composition.The guidewires can serve as an assist-element of the valve system, andcan be removed after valve implantation. After filling the housing, bothwire and catheter can be pulled out of the housing.

In some embodiments, a housing is in the form of a cavity (e.g., partialcavity or through cavity). The cavity can be created by ablatingcavities (e.g., partial cavities and/or through cavities) in the stentframework of the valve system. These cavities can be located on theoutward facing surfaces and/or the sidewalls. Referring to FIGS. 5A and5B, a stent strut 502's width can be made wider at the location of eachcavity 504. FIG. 5B is a cross-sectional side view of a stent strut 502with the partial cavity 504.

In some embodiments, the housing can be positioned on the outsidesurface of the tubular expandable stent, around a circumference of thevalve. The housing can span the entire length of the tubular expandablestent, or can span less than the entire length (e.g., less than or about90%, less than or about 80%, less than or about 70%, less than or about60%, less than or about 50%, less than or about 40%, less than or about30%, less than or about 20%, or less than or about 10% of the fulllength) of the tubular expandable stent, so long as the housing covers alength around the circumference of the valve. The housing can span thethickness of the valve, and when implanted, can fully cover a nativevalve that is now positioned between a body vessel and the heart valvesystem.

In use, the vascular valve system can be implanted into a vessel via aTAVI procedure. When expanded and implanted into a vessel, a hydrogelcoating can be pressed against a native calcified valve, or a hydrogelcomposition can be injected into a housing surrounding the vascularvalve system, which presses against a native calcified valve. Loosenedcalcium deposits can be captured by the hydrogel, and thecalcium-chelating agent can bind to calcium in the calcium deposits. Thecalcium-calcium chelating agent complex can leach out of the hydrogeland be removed from the calcified valve with bodily fluids (e.g.,blood). In some embodiments, when the calcium-chelating agent iscovalently bound to a hydrogel, the covalent bond can be cleaved underphysiological conditions, and the calcium—calcium chelating agent can bereleased from the hydrogel and removed from the calcified valve withbodily fluids.

In some embodiments, micro-magnets can be embedded near the bottom ofthe vascular valve system, within and/or against a polymer skirt. Forexample, the micro-magnets can be embedded on the inner facing surfaceand/or outer surface. The micro-magnets can help localize the deliveryof therapeutic and/or calcium-chelating agent-encapsulating magneticparticles. For example, magnetic microspheres can be formed of ahydrogel (see, e.g., supra) in which a magnetizable material, such asmagnetite, and a drug are embedded. The microspheres can be injectedinto a space between the polymer inner skirt and a native vessel (e.g.,blood vessel). In a magnetic system, the drug and/or calcium chelatingagent can be re-loaded from time to time, or more of the drug and/orcalcium chelating agent can be administered at an area having the mostcalcifications. In some embodiments, a sequence of the same or differentdrugs and chelators can be administered at different time points.

In some embodiments, a hydrogel coating is applied by spray coating asubstrate (e.g., a vascular valve system) with a solution includingpolymers (e.g., hydrogel-forming polymers), calcium chelators,acidifying agents, and solvents. In some embodiments, the solution caninclude one or more therapeutic agents. The solvents can includetetrahydrofuran, methanol, acetone, chloroform, other volatile solvents,and/or water. A vascular valve system can be coated either in itsexpanded state, contracted state, or semi-contracted state.

In some embodiments, the hydrogel coating is applied by electro-sprayinga substrate (e.g., a vascular valve system) with a solution includingpolymers (e.g., hydrogel-forming polymers), calcium chelators,acidifying agents, and solvents. Electrospraying can create a fibernetwork of hydrogel. In particular, by controlling the voltage,flow-rate, concentration of polymers in the spray fluid, the viscosityof the spray fluid, and the distance of the nozzle from the surface ofthe substrate, the width or diameter of the fibers formed during thespinning process can be controlled. Environmental factors, such astemperature, pressure, solvent vapor pressure, can also determine thediameter of the fibers.

In some embodiments, the hydrogel coating can include one or morepolymers, which can, for example, include hydrogel-forming polymers andpolymers that do not form hydrogels. Examples of polymers includewithout limitation oligo(amidoamine/β-amino ester), methyl cellulose,collagen, gelatin, chitosan, hyaluronic acid, chondroitin sulfate,alginate, agar, agarose, fibrin, albumin, polyethylene glycol,polyethylene oxide, polyvinyl alcohol, polypropylene fumarate),oligo(polyethylene glycol) fumarate, poly(N-isopropylacrylamide),polypropylene oxide, poly(aldehyde guluronate), polylactic acid,polyglycolic acid, poly(lactic-co-glycolic) acid, polyanhydride (e.g.,poly(sebacic acid-co-1,3-bis(p-carboxyphenoxy)propane) (P(CPP-SA)),combinations thereof, and/or copolymers thereof. The hydrogelcomposition can be crosslinkable, for example, the hydrogel compositioncan include polymers such as polyethylene glycol diacrylate (PEGDA) andpoly(ethylene glycol)dimethacrylate (PEGDMA). In some embodiments,crosslinkable hydrogels can be crosslinked ex vivo or in situ. Examplesof crosslinking include, for example, reversible or irreversiblechemical and/or physical crosslinking In some embodiments, biodegradablegels can be made by mixing polyanions and polycations, for exampledextran or heparin (anions) with eitherpoly(vinylbenzyltrimethyl)-ammonium hydroxide or chitosan. In certainembodiments, an in-situ crosslinking reaction can occur without heat orradiation. For example, systems that can be gelated bystereo-complexation like PEG-(PLA) or PEG-PLA-PEG are suitable. In someembodiments, the polymers can degrade and be removed from the treatmentsite within a defined period of time (e.g., for a time period of one dayto one week, for a month, for a year, or more). In some embodiments,after release of the calcium-chelating agent is complete, the hydrogeldegrades and disperses from the treatment site.

In some embodiments, a combination of coating methods can be used todeposit various hydrogels, polymers, and/or therapeutic agents, inaddition to the deposition methods described above. For example, methodssuch as conventional nozzle or ultrasonic nozzle spraying, dipping,rolling, electrostatic deposition, and a batch process such as airsuspension, pancoating or ultrasonic mist spraying can be used to coatthe vascular valve system.

In some embodiments, it may be desirable to roughen a surface ofinterest before performing depositions described herein. For example, asurface may be roughened to provide a series of nooks or invaginationson/within the surface. Any surface may be roughened, e.g., a metallic,polymeric or ceramic surface. Surfaces can be roughened using anytechnique known in the art. Particularly useful methods for rougheningsurfaces, such as the surfaces of a stent, are described, e.g., in U.S.Ser. No. 12/205,004, which is hereby incorporated by reference.

Further, as will be appreciated by skilled practitioners, coatingsdescribed herein can be deposited on an entire surface of a device oronto only part of a surface. This can be accomplished using masks toshield the portions on which coatings are not to be deposited. Further,with regard to vascular valve systems, it may be desirable to depositonly on the abluminal surface of the vascular valve system. Thisconstruction may be accomplished by, e.g. coating the vascular valvesystem before forming the fenestrations. In other embodiments, it may bedesirable to deposit only on abluminal and cutface surfaces of thevascular valve system. This construction may be accomplished by, e.g.,depositing on a vascular valve system containing a mandrel, whichshields the luminal surfaces.

The hydrogels can include a therapeutic agent, such as paclitaxel,everolimus, rapamycin, biolimus, zotarolimus, tacrolimus, sirolimus,tacrolimus, heparin, diclofenac, and/or aspirin. The terms “therapeuticagent”, “pharmaceutically active agent”, “pharmaceutically activematerial”, “pharmaceutically active ingredient”, “drug” and otherrelated terms may be used interchangeably herein and include, but arenot limited to, small organic molecules, peptides, oligopeptides,proteins, nucleic acids, oligonucleotides, genetic therapeutic agents,non-genetic therapeutic agents, vectors for delivery of genetictherapeutic agents, cells, and therapeutic agents identified ascandidates for vascular treatment regimens, for example, as agents thatreduce or inhibit restenosis. By small organic molecule is meant anorganic molecule having 50 or fewer carbon atoms, and fewer than 100non-hydrogen atoms in total. The therapeutic agent can be amorphous.

Exemplary non-genetic therapeutic agents include anti-thrombogenicagents such as heparin, heparin derivatives, prostaglandin (includingmicellar prostaglandin E1), urokinase, and PPack (dextrophenylalanineproline arginine chloromethylketone); anti-proliferative agents such asenoxaparin and angiopeptin, monoclonal antibodies capable of blockingsmooth muscle cell proliferation, hirudin, and acetylsalicylic acid;anti-inflammatory agents such as dexamethasone, rosiglitazone,prednisolone, corticosterone, budesonide, estrogen, estrodiol,sulfasalazine, acetylsalicylic acid, mycophenolic acid, and mesalamine;anti-neoplastic/anti-proliferative/anti-mitotic agents such aspaclitaxel, epothilone, cladribine, 5-fluorouracil, methotrexate,doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine,vincristine, epothilones, endostatin, trapidil, halofuginone, andangiostatin; anti-cancer agents such as antisense inhibitors of c-myconcogene; antimicrobial agents such as triclosan, cephalosporins,aminoglycosides, nitrofurantoin, silver ions, compounds, or salts;biofilm synthesis inhibitors such as non-steroidal anti-inflammatoryagents; antibiotics such as gentamycin, rifampin, minocyclin, andciprofloxacin; antibodies including chimeric antibodies and antibodyfragments; anesthetic agents such as lidocaine, bupivacaine, andropivacaine; nitric oxide; nitric oxide (NO) donors such as linsidomine,molsidomine, L-arginine, NO-carbohydrate adducts, polymeric oroligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Argchloromethyl ketone, an RGD peptide-containing compound, heparin,antithrombin compounds, platelet receptor antagonists, anti-thrombinantibodies, anti-platelet receptor antibodies, enoxaparin, hirudin,warfarin sodium, Dicumarol, aspirin, prostaglandin inhibitors, plateletaggregation inhibitors such as cilostazol and tick antiplatelet factors;vascular cell growth promotors such as growth factors, transcriptionalactivators, and translational promotors; vascular cell growth inhibitorssuch as growth factor inhibitors, growth factor receptor antagonists,transcriptional repressors, translational repressors, replicationinhibitors, inhibitory antibodies, antibodies directed against growthfactors, bifunctional molecules consisting of a growth factor and acytotoxin, bifunctional molecules consisting of an antibody and acytotoxin; cholesterol-lowering agents; vasodilating agents; agentswhich interfere with endogenous vascoactive mechanisms; inhibitors ofheat shock proteins such as geldanamycin; angiotensin converting enzyme(ACE) inhibitors; beta-blockers; βAR kinase (βARK) inhibitors;phospholamban inhibitors; protein bound particle drugs such asABRAXANE™; structural protein (e.g., collagen) cross-link breakers suchas alagebrium (ALT-711); and/or any combinations and prodrugs of theabove.

Exemplary biomolecules include peptides, polypeptides and proteins;oligonucleotides; nucleic acids such as double or single stranded DNA(including naked and cDNA), RNA, antisense nucleic acids such asantisense DNA and RNA, small interfering RNA (siRNA), and ribozymes;genes; carbohydrates; angiogenic factors including growth factors; cellcycle inhibitors; and anti-restenosis agents. Nucleic acids may beincorporated into delivery systems such as, for example, vectors(including viral vectors), plasmids or liposomes.

Non-limiting examples of proteins include serca-2 protein, monocytechemoattractant proteins (MCP-1) and bone morphogenic proteins (“BMPs”),such as, for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (VGR-1), BMP-7(OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, andBMP-15. Preferred BMPs are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, andBMP-7. These BMPs can be provided as homodimers, heterodimers, orcombinations thereof, alone or together with other molecules.Alternatively, or in addition, molecules capable of inducing an upstreamor downstream effect of a BMP can be provided. Such molecules includeany of the “hedgehog” proteins, or the DNAs encoding them. Non-limitingexamples of genes include survival genes that protect against celldeath, such as antiapoptotic Bcl-2 family factors and Akt kinase; serca2 gene; and combinations thereof. Non-limiting examples of angiogenicfactors include acidic and basic fibroblast growth factors, vascularendothelial growth factor, epidermal growth factor, transforming growthfactors α and β, platelet-derived endothelial growth factor,platelet-derived growth factor, tumor necrosis factor α, hepatocytegrowth factor, and insulin-like growth factor. A non-limiting example ofa cell cycle inhibitor is a cathepsin D (CD) inhibitor. Non-limitingexamples of anti-restenosis agents include p15, p16, p18, p19, p21, p27,p53, p57, Rb, nFkB and E2F decoys, thymidine kinase and combinationsthereof and other agents useful for interfering with cell proliferation.

Exemplary small molecules include hormones, nucleotides, amino acids,sugars, and lipids and compounds having a molecular weight of less than100 kD.

Any vascular valve system described herein can be dyed or renderedradiopaque by addition of, e.g., radiopaque materials such as bariumsulfate, platinum or gold, or by coating with a radiopaque material. Thevascular valve system can include (e.g., be manufactured from) metallicmaterials, such as stainless steel (e.g., 316L, BioDur® 108 (UNSS29108), and 304L stainless steel, and an alloy including stainlesssteel and 5-60% by weight of one or more radiopaque elements (e.g., Pt,Ir, Au, W) (PERSS®) as described in US-2003-0018380-A1,US-2002-0144757-A1, and US-2003-0077200-A1), Nitinol (a nickel-titaniumalloy), cobalt alloys such as Elgiloy, L605 alloys, MP35N, titanium,titanium alloys (e.g., Ti-6Al-4V, Ti-50Ta, Ti-10Ir), platinum, platinumalloys, niobium, niobium alloys (e.g., Nb-1Zr) Co-28Cr-6Mo, tantalum,and tantalum alloys. Other examples of materials are described incommonly assigned U.S. application Ser. No. 10/672,891, filed Sep. 26,2003; and U.S. application Ser. No. 11/035,316, filed Jan. 3, 2005.Other materials include elastic biocompatible metal such as asuperelastic or pseudo-elastic metal alloy, as described, for example,in Schetsky, L. McDonald, “Shape Memory Alloys”, Encyclopedia ofChemical Technology (3rd ed.), John Wiley & Sons, 1982, vol. 20. pp.726-736; and commonly assigned U.S. application Ser. No. 10/346,487,filed Jan. 17, 2003.

EXAMPLES Example 1 Heart Valve with Internal Housing of PolyethyleneTerephthalate and an External Electrospun Fiber Network of PLGA

A finished heart valve with a PET outer skirt is first being providedwith a series of empty depots (i.e., pockets, or housings). Referring toFIG. 6A, a balloon expandable heart valve with a polyethyleneterephthalate (PET) inner skirt 602, mounted by stitches 604 on theinside of a stent frame, is used as a starting point. A Ultra-thinPolyester (Mylar®) 0.00014″ (3.6 μm) PET foil (SPI Supplies WestChester, Pa.) is cut into a 15 mm strip by 200 mm and placed flat on astainless steel surface. In some embodiments, the length of theultra-thin polyester is not important, as long as it is longer than thepolymer skirt film. The polyester is glued with ethyl cyanoacrylate tothe skirt and cut to equal length as the skirt before being sewn to thestent, and the end (2 cm) of a stainless steel wire (0.014″ diameter) isinserted in between the skirt and foil. The film is provided with 20micrometer diameter holes at a ratio of 10% of the total surface areausing a mask in combination with a KrF laser (248 nm) (Lambda PhysikEMG201, 30 ns), set a laser fluence of 35 mJ/cm². The perforated film606 is glued circumferentially to the skirt before mounting the skirt tothe stent. In other words, the laser ablated film is glued as stripes ontop and bottom to the PET skirt, and then sewn as shown in FIG. 6B onthe inside of the stent.

An electrospun layer is then created on the external surface of theheart valve. A 100 ml solution is prepared at room temperature, thesolution includes 3:1 THF:DMF and 3 g/ml PLGA (Sigma Aldrich). Thesolution is stirred for 24 hours. The heart valve is placed on a Teflonturn table which allows rotation of the valve at a speed of 12 RPM,rotating the table repeatedly for 5 clockwise rotations and 5counterclockwise rotations to avoid disconnecting of the ground wire.The housing of the heart valve is connected by a vertical wire toground. A 60 mL syringe is filled with the solution and a Teflon tubingis connected between syringe and a 35 gauge needle. The point of theneedle is placed 12 cm from the housing. The syringe (60 ml) is placedin a syringe pump (NE-1000 Programmable Single Syringe Pump: New EraPump Systems Inc.). The syringe pump is run at 2 ml/hr. The needle isconnected to a high voltage supply (CZE1000R, Spellman United Kingdom,West Sussex). The high voltage supply is set at 12 kV and the process isrun for approx. 10 minutes. The solution is sprayed over the bottom 10mm of the housing (masking the area where there is no skirt) and forms anetwork of about 4 mm thick at a volume density of about 10%.

The whole assembly is crimped onto a 25 mm balloon and expanded at theposition of the original native heart valve. After removing the deliverysystem of the valve, a Fr 3 catheter can be inserted over the wire goinginto the depots. A thermo-sensitive hydrogel solution was made by slowlymixing 35% by weight Pluronic F-127 (Sigma-Aldrich) in 5 degrees Celsiuswater and adding 2 mg/ml L-Ascorbic acid (Sigma-Aldrich). The solutionwas maintained at 5 degrees Celsius before injecting 1.6 ml into thedepots of placed heart valve. The delivery tube was pulled out after 60seconds.

Example 2 Heart Valve with Ablated Cavities in a Stent Framework,Functioning as Reservoirs for Calcium Chelators

Referring to FIG. 7, a finished stainless steel heart valve stent frame700 is being provided with a series of empty cavities 702 on stent strut704. The metal housing is provided with 50 micrometer diameter, 100micrometer deep cavities using an excimer laser (351 nm) (CoherentXantos XS-500-351 nm, 16 ns pulse width), set at a laser fluence of 100J/cm², utilizing sequences of 300 pulses). The cavities are located atthe outside of the housing, centered along the middle axis of the strutswith a distance between the holes of 300 micrometer. Providing 20cavities between each connection point.

A 100 ml solution is prepared at room temperature, the solution includes3:1 THF:DMF, 3 g/ml PLGA (Sigma Aldrich), and 5% by weight ofEverolimus. The solution is stirred for 24 hours and inkjet printed inthe cavities using a “Autodrop” system from Microdrop (MicrodropTechnologies GmbH, Muehlenweg 143, D-22844 Norderstedt Germany), afterwhich further assembly is carried out.

Example 3 Heart Valve System Including Embedded Magnetic Microspheres

Six Neodynium micro magnets are purchased from BJA magnetics (BJAMagnetics, Leominster, Mass.), in the form of discs having a 0.040″outer diameter, a 0.01″ inner diameter, and 0.006″ thickness. Themagnets are provided by the manufacturer with a parylene coating and areglued to a polyethylene terephthalate skirt of a balloon expandablevalve system, using a medical grade MP-21HP two-component primer andinstant adhesive from Loctite (Loctite, Nieuwegein, Netherlands). Thelocation (and small size) of two of the six micromagnets 802 is shown inFIG. 8. The PET skirt 804, located within a stent frame 806, isperforated in the area surrounding the magnets with 10 times 0.005″diameter holes using an ablation laser (e.g., an excimer 356 nm laser).The valve is crimped on a balloon and implanted per normal procedure.

A Renegade Hi-Flow Fr 3. Microcatheter is provided at the tip with aParylene coated iron markerband, which is attached to the tip of themicrocatheter using a PET shrinktube (Advanced polymers, Salem, N.H.), 2mm located from the distal end. The microcatheter is inserted over a0.14″ Guide Wire (Synchro2, Boston Scientific) to be near the locationof the micromagnets. The magnetic attraction between the micromagnetsand the iron markerbands is used to keep the tip of the microcatheterlocated near the magnets.

Magnetic biodegradable PLGA particles loaded with Everolimus as made perrecipe as described by Asmatulu, R. et al., Drug-Carrying MagneticNanocomposite Particles for Potential Drug Delivery Systems, Journal ofNanotechnology, Volume 2009 (2009), Article ID 238536, hereinincorporated by reference in its entirety, were produced and injected(dissolved in saline) via the micro-catheter. The magnetic particles candiffuse out of the perforated holes in the PET skirt to the area betweenthe skirt and the native blood vessel. The magnetic particles can remainin the area between the skirt and the native blood vessel, near theproximity of the micro magnets.

All non-patent literature publications, patent applications, patentapplication publications, and patents, referred to in the instantapplication are incorporated herein by reference in their entirety.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

What is claimed is:
 1. A vascular valve system comprising: an expandablestent comprising an outer surface and a lumen; a valve comprising aplurality of leaflets, wherein the valve is disposed within the lumenand coupled to the expandable stent; and a layer disposed on at least aportion of the outer surface of the stent, the layer comprising ahydrogel, a calcium-chelating agent, and an acidifying agent.
 2. Thevascular valve system of claim 1, wherein the valve comprises at leasttwo leaflets.
 3. The vascular valve system of claim 1, wherein the valvecomprises three leaflets.
 4. The vascular valve system of claim 1,wherein the valve comprises porcine pericardium or a polymeric material.5. The vascular valve system of claim 1, wherein the valve is attachedto the stent with a plurality of sutures.
 6. The vascular valve systemof claim 1, wherein the layer is disposed around a circumference of thevalve.
 7. The vascular valve system of claim 1, wherein the hydrogel isin the form of a plurality of fibers, a coating, a sheet, a film, or aviscous liquid.
 8. The vascular valve system of claim 1, wherein thehydrogel is selected from the group consisting ofoligo(amidoamine/β-amino ester), gelatin, methyl cellulose, collagen,gelatin, chitosan, hyaluronic acid, chondroitin sulfate, alginate, agar,agarose, fibrin, polyethylene glycol, polyethylene oxide, polyvinylalcohol, polypropylene fumarate), oligo(polyethylene glycol) fumarate,poly(N-isopropylacrylamide), polypropylene oxide, poly(aldehydeguluronate), polylactic acid, polyglycolic acid,poly(lactic-co-glycolic) acid, polyanhydride, combinations thereof, andcopolymers thereof.
 9. The vascular valve system of claim 1, wherein thecalcium-chelating agent is selected from the group consisting ofethylene diamine tetraacetic acid, phosphonates,1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, ethyleneglycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid,trans-1,2-cyclohexanediaminetetraacetic acid,N-hydroxyethylenediaminetriacetic acid, diethylenetriaminepentaaceticacid, and glycine.
 10. The vascular valve system of claim 1, wherein thecalcium-chelating agent is covalently bound to the hydrogel.
 11. Thevascular valve system of claim 1, wherein the hydrogel comprises fromone percent to ten percent by weight of the calcium-chelating agent. 12.The vascular valve system of claim 1, wherein the acidifying agent isselected from the group consisting of citric acid, ascorbic acid, aceticacid, lactic acid, and any combination thereof.
 13. The vascular valvesystem of claim 1, wherein the acidifying agent is covalently bound tothe hydrogel.
 14. The vascular valve system of claim 1, wherein thehydrogel comprises from 0.5 percent to 20 percent by weight of theacidifying agent.
 15. The method of claim 1, wherein the hydrogel iscrosslinkable.
 16. The method of claim 1, wherein the hydrogel comprisespolyethylene glycol diacrylate and poly(ethylene glycol)dimethacrylate.17. A vascular valve system comprising: an expandable stent comprisingan outer surface and a lumen; a valve comprising a plurality ofleaflets, wherein the valve is disposed within the lumen and coupled tothe expandable stent; and a permeable housing disposed on one or moreleaflets, or around a portion of the outer surface of the stent, orboth.
 18. The vascular valve of claim 17, wherein the permeable housingis disposed around a circumference of the valve.
 19. The vascular valvesystem of claim 17, wherein a hydrogel, a calcium-chelating agent, andan acidifying agent is disposed within the housing.
 20. The vascularvalve system of claim 19, wherein the hydrogel is selected from thegroup consisting of oligo(amidoamine/β-amino ester), gelatin, methylcellulose, collagen, gelatin, chitosan, hyaluronic acid, chondroitinsulfate, alginate, agar, agarose, fibrin, polyethylene glycol,polyethylene oxide, polyvinyl alcohol, polypropylene fumarate),oligo(polyethylene glycol) fumarate, poly(N-isopropylacrylamide),polypropylene oxide, poly(aldehyde guluronate), polylactic acid,polyglycolic acid, poly(lactic-co-glycolic) acid, polyanhydride,combinations thereof, and copolymers thereof.
 21. The vascular valvesystem of claim 19, wherein the calcium-chelating agent is selected fromthe group consisting of ethylene diamine tetraacetic acid, phosphonates,1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, ethyleneglycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid,trans-1,2-cyclohexanediaminetetraacetic acid,N-hydroxyethylenediaminetriacetic acid, diethylenetriaminepentaaceticacid, and glycine.
 22. The vascular valve system of claim 19, whereinthe acidifying agent is selected from the group consisting of citricacid, ascorbic acid, acetic acid, lactic acid, and any combinationthereof.
 23. The vascular valve system of claim 19, wherein the hydrogelis crosslinkable.
 24. The vascular valve system of claim 23, wherein thehydrogel comprises polyethylene glycol diacrylate and poly(ethyleneglycol)dimethacrylate.
 25. The vascular valve system of claim 17,further comprising a layer disposed on at least a portion of the outersurface of the stent, the layer comprising a hydrogel, acalcium-chelating agent, and an acidifying agent.
 26. A method ofreplacing a heart valve, comprising: implanting the vascular valvesystem of claim 17; injecting a solution comprising a hydrogel, acalcium-chelating agent, and an acidifying agent into the permeablehousing.